Cefpodixime proxetil

ABSTRACT

The present invention relates to an improved and cost effective process for the industrial manufacture of cefpodoxime proxetil. More specifically, the present invention relates to the preparation of cefpodoxime proxetil of high purity and yield. The process comprises a) dissolving impure cefpodoxime proxetil or adding a solution containing cefpodoxime proxetil into a polar organic solvent or mixture(s) thereof, optionally reducing the solvent by concentration, and adding into a non-polar organic solvent or mixture(s) thereof to precipitate the solid; and b) dissolving the solid obtained from the above step into water-miscible polar organic solvent, optionally reducing the solvent by concentration, adding it into water to obtain the pure cefpodoxime proxetil.

FIELD OF THE INVENTION

The present invention relates to an improved and cost effective processfor the industrial manufacture of cefpodoxime proxetil. Morespecifically, the present invention relates to the preparation ofcefpodoxime proxetil of high purity and yield.

BACKGROUND OF THE INVENTION

Chemically, cefpodoxime proxetil is 1-isopropoxycarbonyloxyethyl(6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem-4-carboxylateof Formula I and is disclosed in U.S. Pat. No. 4,486,425.

Cefpodoxime proxetil is one of the limited class of third generationcephalosporin derivatives which can be administered orally as it isreadily adsorbed through the digestive tract and which is then readilyhydrolyzed and converted in vivo to the corresponding carboxylic acidwhich, in turn, shows outstanding antibacterial activity against bothgram-positive and gram-negative bacteria.

Pharmaceutical compounds are required in highly pure form because of thefear of unknown and potentially harmful effects of impurities. Forpurposes of patient' safety, it is highly desirable to limit the amountof impurities present in any medicament administered to a patient. Thisis achieved by either devising a process for or by additionalpurification steps like chromatography or recrystallization etc. Thepurity of intermediates and raw materials is essential for obtaining thetarget pharmaceutical compounds in high yield and purity.

A number of methods have been outlined in U.S. Pat. No. 4,486,425 forthe synthesis of the cefpodoxime esters. However, in each of thesemethods, esterification of the carboxylic acids of the cephem ringresults in impurities which have to be removed using silica gel columnchromatography, as illustrated in the examples. U.S. Pat. Nos. 4,482,710and 5,461,043 also illustrate the synthesis of cefpodoxime proxetilusing methods outlined in U.S. Pat. No. 4,486,425 which employchromatography after the esterification step to remove impurities and toget pure cefpodoxime proxetil.

PCT application WO 99/35149 describes the preparation of cefpodoximeproxetil with a focus on the adjustment of diastereoisomeric ratio ofthe two diastereoisomers of cefpodoxime proxetil in the product mixture.Although, the process illustrated in this PCT application does not usechromatographic techniques for isolation of products, the processinvolves additional steps of protection and deprotection at the aminoposition of the thiazolyl moiety.

Thus none of the prior art processes are satisfactory for the reasonsdescribed above.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a cost effective andindustrially advantageous process for the purification and isolation ofthe desired syn isomer of cefpodoxime proxetil in high purity and yieldthus, obviating the need for chromatography or additional steps ofprotection and deprotection.

Accordingly, the present invention provides a novel and industriallyadvantageous process for isolating the pure cefpodoxime proxetil ofFormula I

which removes the common impurities (the Δ²-isomer of Formula II andanti-isomer of Formula III as shown below:

formed during the esterification reaction. Further, the process of thepresent invention also has the capabilities to eliminate the other sideproducts formed during the esterification step i.e. the reaction of1-iodoethylisopropyl carbonate of Formula IV

with the unprotected amino group of the thiazolyl moiety of cefpodoximeproxetil of Formula I. Thus, the product obtained by following thepresent process is highly pure without the use of chromatography orwithout carrying out additional steps of protection and deprotection.

More specifically, the present invention relates to a process for thepurification and isolation of pure cefpodoxime proxetil of Formula I,comprising the steps:

-   -   a) dissolving impure cefpodoxime proxetil or adding a solution        containing cefpodoxime proxetil into a polar organic solvent or        mixture(s) thereof, optionally reducing the solvent by        concentration, and adding into a non-polar organic solvent or        mixture(s) thereof to precipitate the solid;    -   b) dissolving the solid obtained from the above step into        water-miscible polar organic solvent, optionally reducing the        solvent by concentration, adding it into water to obtain the        pure cefpodoxime proxetil.

The scope of the present invention also covers the process for obtainingthe pure cefpodoxime proxetil wherein the order of purification andisolation i.e. steps (a) and (b) is reversed.

In turn, cefpodoxime proxetil of Formula I may be obtained in situ byreacting 7-(2-(2-aminothiazol-4-yl)-2-methoxy-3-cephem carboxylic acidi.e. cefpodoxime acid (prepared as per the general process described inEP 29557) of Formula V or salt thereof,

with 1-iodoethyl isopropylcarbonate of Formula IV,

in the presence of a base which is followed by the purification andisolation of pure cefpodoxime proxetil as per the steps (a) and (b),above.

In the meaning of the present invention, the term “water-miscible” shallrefer to organic solvents which show essentially unlimited, preferably100% miscibility with water. The polar organic solvents may have limitedwater miscibility and the term “limited miscibility” shall also includewater-immiscible organic solvents.

Example for water-miscible organic solvents include lower alcohols suchas methanol, ethanol and isopropanol; lower alkyl ketones such asacetone, lower alkyl glycol ethers such as methyl glycol; dipolaraprotic solvents such as N,N-dimethyl formamide (DMF),N,N-dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO) and cyclicethers such as tetrahydrofuran, dioxane, or mixture(s) thereof.Particularly preferred solvents are methanol, ethanol, isopropanol, andacetone.

Examples of polar organic solvents having limited miscibility in waterinclude carboxylic acid esters such as ethyl acetate, higher alkylketones such as methylisobutyl ketone; chlorinated hydrocarbons, such asdichloromethane or mixture(s) thereof. Particularly preferred solventsare ethyl acetate and dicholoromethane. Suitable non-polar organicsolvents include hydrocarbons such as hexane, xylene; higher alkylethers such as diisopropyl ether, cyclic hydrocarbons such ascyclohexane, or mixture(s) thereof. Particularly preferred arediisopropyl ether and cyclohexane.

It has been observed that slow, preferably dropwise, addition of thesolution into a well stirred non-polar solvent or water (in first andsecond precipitation, respectively) gives the desirable purity of theproduct while adding the solution all at once, may result in lumps or agummy product.

Cefpodoxime acid of Formula V used in the esterification reaction may bein the form of a salt, for example, an alkali metal salt, such as sodiumor potassium salt, an ammonium salt or salt with nitrogen containingbases, such as triethylamine and dicyclohexylamine.

The base may be selected from the group consisting of inorganic such aspotassium carbonate, sodium carbonate and sodium bicarbonate, or organicsuch as triethylamine, dicyclohexylamine,1,8-diazabicyclo[5,4.0]undec-7-ene (DBU) and N,N-dimethylaniline or amixture thereof. If the starting compound of Formula V is in the form ofa carboxylic acid salt such as sodium or potassium, it may be used inthe reaction as such, without any base.

The reaction is performed in the presence of a solvent. Suitablesolvents include dimethylformamide, dimethylacetamide,dimethylsulphoxide, tetrahydrofuran, dichloromethane, ethylacetate,acetonitrile or mixture(s) thereof. The reaction is conducted at ambienttemperature or with cooling, preferably at −10 to 0° C.

The reaction mixture containing cefpodoxime proxetil in situ is thenpoured in to a polar organic solvent having limited miscibility orsolubility in water and washed successively with aqueous solutions ofhydrochloric acid, sodium bicarbonate, sodium thiosulphate and sodiumchloride in sequence.

The washed organic layer is concentrated and is then added into anon-polar organic solvent to accomplish the first precipitation.

The product is further purified by dissolving the product in a watermiscible and optionally subjecting it to carbon treatment followed bypartial concentration and addition of the concentrated layer into waterto effect the second precipitation and obtain highly pure cefpodoximeproxetil. The separated solid is filtered and dried.

The compounds of Formula I may be obtained in the form of acid additionsalts with pharmaceutically acceptable acids, for example inorganicacids such as hydrochloric acid, sulfuric acid and phosphoric acid ororganic acids such as malonic acid, oxalic acid and tartaric acid.

DETAILED DESCRIPTION OF THE INVENTION

In the following section one preferred embodiment is described by way ofexample to illustrate the process of this invention. However, it is notintended in any way to limit the scope of the present invention.

EXAMPLE

Preparation of Cefpodoxime Proxetil in Situ

10 g of (6R,7R)7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(methoxymethyl)3-cephem-4-carboxylicacid was added to 60 ml of N,N-dimethylacetamide and the mixture wascooled to −8° C. 1,8-diazabicyclo[5,4.0]undec-7-ene (DBU) (3.33 g) wasadded followed by addition of 1-iodoethyl isopropyl carbonate (5.85 g)at −8 to −5° C. The reaction mixture was stirred for 45 min at the sametemperature.

The reaction mixture thus obtained was poured into ethyl acetate (300ml) followed by the addition of water (300 ml) at 20–22° C. The mixturewas stirred for 10 min and the organic layer was separated. The organiclayer was then washed successively with aqueous hydrochloric acid,aqueous sodium thiosulphate, and finally with aqueous sodium chloride.

Purification and Isolation of Pharmaceutical Grade Cefpodoxime Proxetil

Step—(a)

The ethyl acetate layer as obtained above was concentrated to about 40ml at 30–35° C. under reduced pressure and added to cyclohexane (300 ml)under stirring at 25° C during about 30 minutes. The precipitated solidwas then filtered and washed with cyclohexane.

Step (b)

The wet product from Step (a) was added to methanol (40 ml) at roomtemperature to obtain a solution and was concentrated at 30–35° C. underreduced pressure to about 30 ml. It was then added to water (180 ml) in15 minutes at 20–25° C. to obtain a solid which was filtered and washedwith a cold mixture of methanol and water (1:6 v/v, 20 ml). The filteredsolid was dried to obtain 9 g of pure cefpodoxime proxetil.(Diastereoisomeric mixture ratio B/A+B=0.52 where B is the more polarisomer, Assay: 98%).

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

1. A process for the purification and isolation of pure cefpodoximeproxetil of Formula I, or pharmaceutically acceptable salts thereof,

comprising: (a) dissolving impure cefpodoxime proxetil or adding asolution containing cefpodoxime proxetil into a polar organic solvent ormixture(s) thereof, optionally reducing the solvent by concentration,and adding into a non-polar organic solvent or mixture(s) thereof toprecipitate the solid; and (b) dissolving the solid obtained from theabove step into water-miscible polar organic solvent, optionallyreducing the solvent by concentration, and adding into water to obtainthe pure cefpodoxime proxetil.
 2. The process according to claim 1,wherein cefpodoxime proxetil is obtained by reacting cefpodoxime acid ofFormula V,

or a salt thereof with 1-iodoethyl isopropyl carbonate of Formula IV,

optionally in the presence of a base.
 3. The process according to claim1 or 2, wherein the solution obtained after dissolving cefpodoximeproxetil or by adding a solution containing cefpodoxime proxetil into apolar organic solvent is washed with aqueous acidic and/or basicsolution.
 4. The process according to claim 1 or 2, wherein the polarorganic solvent has limited miscibility in water.
 5. The processaccording to claim 4 wherein the polar organic solvent having limitedmiscibility in water is ethyl acetate or dichloromethane.
 6. The processaccording to claim 1 or 2 wherein the non-polar organic solvent isdiisopropyl ether or cyclic hydrocarbon.
 7. The process according toclaim 6 wherein the cyclic hydrocarbon is cyclohexane.
 8. The processaccording to claim 1 or 2 wherein the water miscible organic solvent ismethanol, ethanol, isopropanol, or acetone.
 9. The process according toclaim 8 wherein the water miscible organic solvent is methanol.
 10. Theprocess according to claim 2 wherein the compound of Formula V is asodium salt of cefpodoxime acid.
 11. The process according to claim 2wherein the base used is selected from the group consisting of potassiumcarbonate, sodium carbonate, dicyclohexylamine, 1,8-diazabicylco[5.4.0]undec-7-ene (DBU), and mixture(s) thereof.
 12. The processaccording to claim 2, wherein the reaction is performed at −10 to 0° C.